While loss of elastin in the alveolar space is clear and thought to be required for the development of the airspace enlargement that characterizes emphysema, collagen turnover is more complex. In fact, there is a net increase in collagen in COPD, generating many questions including: Does collagen turnover contribute to impaired lung function? Does small airway sub-epithelial collagen deposition cause airflow obstruction? Is this airflow obstruction due to physical obstruction, loss of integrity, and/or hyperreactivity? Since collagen is intrinsically stiffer than elastin, and there appears to be more collagen per cross-sectional area of alveolar wall in emphysema, why is lung compliance in emphysema reduced? Is the collagen fiber itself weaker or is the 3-D structure of the remodeled fiber network altered so as to be more compliant overall? What is the stimulus for collagen biosynthesis? To complicate matters, we present preliminary data which shows that MMP-9 is required for cigarette smoke-related small airway sub-epithelial fibrosis in mice. To address these questions we will test the following overall hypotheses regarding collagen turnover in COPD: 1) Unlike in restrictive fibrotic lung diseases, collagen accumulation in COPD contributes to airflow obstruction via small airway sub-epithelial fibrosis; and 2) MMPs are responsible for both collagen production (gelatinases) and collagen depletion (collagenases). Once we understand the basis for collagen accumulation, and its functional effects in the airway and airspace, we will determine whether MMP (or even collagenase-specific) inhibition is beneficial or harmful in COPD. Experimentally, we will address these issues using a combination of studies loosely termed "genomic physiology." Combining our murine model of cigarette smoke exposure with genetically engineered mice, we will apply sensitive measures of lung physiology and morphometry to define structure-function relationships in COPD. Cell biology and protein chemistry will also be used to determine whether MMP-9 affects fibrosis via growth factor generation or direct cellular fibroproliferation. Together with our collaborators we have just developed mice deficient in MMP-8 and -13, the two major mouse collagenases, and will use them to explore the effects of collagenolytic enzymes in COPD.